Gaucher disease results from biallelic pathogenic variants that cause deficient activity of the lysosomal enzyme glucocerebrosidase. As a consequence, the enzyme's substrate, glucosylceramide, accumulates within macrophages of the liver, spleen, bone marrow, lungs, and other organs. GD is inherited in an autosomal recessive pattern; each child of two carrier parents has a 25% risk of being affected. Gene-specific information is not populated in the known_genes field of this packet. Per GeneReviews, genotype-phenotype correlations in GD are imperfect, with significant clinical overlap across genotype groups precluding specific prognostic conclusions based on genotype alone. Residual enzyme activity levels measured in vitro do not reliably predict disease type or severity. Phenotypic discordance has been reported even among monozygotic twins. Variants that eliminate residual enzyme activity are more commonly associated with the severe neuronopathic forms (types 2 and 3), while variants permitting partial residual activity are more often associated with non-neuronopathic disease. Founder variants account for the higher prevalence observed in Ashkenazi Jewish and certain other populations.

The diagnosis of Gaucher disease is established by finding 0–15% of normal glucocerebrosidase enzyme activity in peripheral blood leukocytes or other nucleated cells, or by the identification of biallelic pathogenic variants through molecular genetic testing, per GeneReviews. Newborn screening for GD is available in some jurisdictions, based on quantification of glucocerebrosidase enzyme activity on dried blood spots. In symptomatic individuals, GD is suspected when characteristic clinical features are present. In adults, type 1 GD is associated with hepatomegaly, splenomegaly, cytopenias, bone disease, and pulmonary disease in the absence of primary neurological involvement. Infantile-onset disease (type 2) features bulbar and pyramidal signs, cognitive impairment, and cytopenias. Childhood-onset disease (type 3) features oculomotor apraxia, seizures, progressive myoclonic epilepsy, and bone disease, per GeneReviews. Differential diagnosis includes other lysosomal storage disorders with overlapping features such as hepatosplenomegaly; GD is distinguishable from these by biochemical enzyme testing and molecular analysis. Autosomal recessive inheritance is consistent with GD; family history of consanguinity may increase the clinical index of suspicion.

Treatment of Gaucher disease is guided by the type and severity of clinical manifestations. Three FDA-approved therapies are listed in this packet's approved_treatments field. ELELYSO (taliglucerase alfa), approved by the FDA in May 2012, and VPRIV (velaglucerase alfa), approved in February 2010, are biologic enzyme replacement therapies administered intravenously. OPFOLDA (miglustat), approved in September 2023, is a substrate reduction therapy administered orally. Per GeneReviews, enzyme replacement therapy has been demonstrated to reverse hematologic and visceral involvement, reduce rates of bone loss, improve bone pain, and reduce bone crises. Individuals with type 1 GD have reported improved health-related quality of life following enzyme replacement therapy. Per GeneReviews, ERT does not alter the neurological disease trajectory in type 2 GD; individuals with pyramidal tract signs are not likely to derive neurological benefit due to blood-brain barrier limitations. Individuals with type 3 GD appear to derive some systemic benefit from ERT, though long-term neurological prognosis remains incompletely characterized. Long-term surveillance encompasses skeletal, hematologic, hepatic, splenic, pulmonary, and—where applicable—neurological manifestations. Management by a multidisciplinary team with expertise in GD is available at Comprehensive Treatment Centers, per GeneReviews. GeneReviews documents nonsteroidal anti-inflammatory drugs as agents associated with bleeding risk in individuals with moderate-to-severe thrombocytopenia, alongside caution regarding anticoagulant use in that context.

The prognosis of Gaucher disease is highly dependent on type and disease severity. Type 1 GD is clinically heterogeneous; a significant proportion of individuals with certain genotypes may remain asymptomatic without coming to medical attention, per GeneReviews, while others develop progressive organ involvement. With available enzyme replacement and substrate reduction therapies, systemic manifestations can be substantially reduced and quality of life improved. Individuals with type 2 GD have a severe course with early neurological deterioration; the natural history is not substantially altered by currently available therapies. Type 3 GD represents a broader spectrum of subacute neurological involvement, and long-term prognosis varies across the heterogeneous subgroup, per GeneReviews. The onset of progressive myoclonic seizures during enzyme replacement therapy is documented as a poor prognostic indicator. Genotype-phenotype correlations remain imperfect, and individual disease trajectories vary considerably even among individuals with the same genotype.

Gaucher disease is an active area of investigation, with numerous clinical trials listed on ClinicalTrials.gov (clinicaltrials.gov/search?cond=Gaucher%20disease). Research approaches documented in GeneReviews include pharmacological chaperone therapy, next-generation enzyme replacement formulations, substrate reduction agents, and gene therapy. Among the investigational approaches described in GeneReviews, venglustat—a brain-penetrant glucosylceramide synthase inhibitor—has been studied in adults with type 3 GD, with preliminary findings of clinical stability in some participants and inconsistent biomarker changes. Ambroxol, a mucolytic agent with proposed glucocerebrosidase chaperone properties, has been evaluated in pilot studies demonstrating increased lymphocyte enzyme activity and decreased cerebrospinal fluid substrate levels. This packet's clinical_trial_details field lists 10 active trials. Individuals and families interested in research participation can search ClinicalTrials.gov for current studies related to Gaucher disease.